The present invention relates to a class of substituted imidazo-pyridine derivatives and to their use in therapy. More particularly, this invention is concerned with imidazo[4,5-b]pyridine analogues which are substituted in the 3-position by a substituted phenyl ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six xcex1 subunits, four xcex2 subunits, three xcex3 subunits, one xcex4 subunit, one xcex5 subunit and two xcfx81 subunits.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an xcex1 subunit, a xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, xcex4, xcex5 and xcfx81 subunits also exist, but are present only to a minor extent in GABAA receptor populations.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex3 subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many others, xcex11xcex22xcex32, xcex12xcex2xcex31, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex14xcex2xcex4, xcex15xcex23xcex32/3, xcex16xcex22 and xcex16xcex2xcex4. Subtype assemblies containing an xcex11 subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.
A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with a xcex2 subunit and xcex32. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.
Two other major populations are the xcex12xcex2xcex32 and xcex13xcex2xcex32/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain xcex15-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at xcex11xcex2xcex32, xcex12xcex2xcex32 or xcex13xcex2xcex32 subunits will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as xe2x80x9cGABAA receptor agonistsxe2x80x9d. The xcex11-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the xcex11 subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the xcex12 and/or xcex13 subunit than with xcex11 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at xcex11 might be employed to reverse sedation or hypnosis caused by xcex11 agonists.
The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.
Further disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss. Selective ligands for GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
EP-A-0616807 describes a class of benzimidazole derivatives which are stated to possess potent benzodiazepine receptor affinity, and thus to be useful in the treatment of convulsions, anxiety, sleep disorders, memory disorders and other disorders sensitive to benzodiazepine receptor binding activity. WO 98/34923 relates to a class of 1-phenylbenzimidazole derivatives, substituted at the meta position of the phenyl ring by a methylene-, carbonyl- or thiocarbonyl-linked amine moiety, which are selective ligands for GABAA receptors and accordingly of benefit in alleviating neurological disorders including anxiety and convulsions. There is, however, no disclosure nor any suggestion in EP-A-0616807 or WO 98/34923 that the benzimidazole nucleus specified therein can be replaced by any other moiety, with in particular no mention being made therein of replacement by the imidazo[4,5-b]pyridine functionality.
EP-A-0563001 describes a class of fused imidazole derivatives which are stated to possess activity as calcium channel blockers. There is, however, no disclosure nor any suggestion in EP-A-0563001 that the compounds described therein might be effective as ligands for GABAA receptors.
The present invention provides a class of imidazo-pyridine derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the xcex12 and/or xcex13 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the xcex12 and/or xcex13 subunit than with the xcex11 subunit. Desirably, the compounds of the invention will exhibit functional selectivity in terms of a selective efficacy for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit.
The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the xcex12 and/or xcex13 subunit, as measured in the assay described hereinbelow, of 200 nM or less, typically of 100 nM or less, and ideally of 20 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit. However, compounds which are not selective in terms of their binding aflinity for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of a selective efficacy for the xcex12 and/or xcex13 subunit relative to the xcex11 subunit.
The present invention provides a compound of formula I, or a salt or prodrug thereof: 
wherein
Y represents a chemical bond, or a methylene (CH2), carbonyl (Cxe2x95x90O), thiocarbonyl (Cxe2x95x90S) or amide (CONH or NHCO) linkage;
Z represents an optionally substituted aryl, heteroaryl or heteroaryl(C1-6)alkyl group, or a group of formula xe2x80x94NR1R2;
R1 and R2 independently represent hydrogen, hydrocarbon or a heterocyclic group; or R1 and R2, together with the intervening nitrogen atom, represent an optionally substituted heterocyclic ring selected from azetidinyl, pyrrolidinyl, piperidinyl piperazinyl, morpholinyl and thiomorpholinyl; and
R3 represents aryl or heteroaryl, either of which groups may be optionally substituted.
The present invention also provides a compound of formula I as depicted above, or a salt or prodrug thereof, wherein
Z represents an optionally substituted heteroaryl or heteroaryl(C1-6)alkyl group, or a group of formula xe2x80x94NR1R2; and
Y, R1, R2 and R3 are as defined above.
Where Z in the compounds of formula I above represents an optionally substituted aryl, heteroaryl or heteroaryl(C1-6)alkyl group, this group may be unsubstituted, or substituted by one or more, typically one or two, substituents. Suitably, the aryl, heteroaryl or heteroaryl(C1-6)alkyl group Z is unsubstituted or monosubstituted. Likewise, the aryl or heteroaryl group R3 may be unsubstituted, or substituted by one or more, typically one or two, substituents. Suitably, the group R3 is unsubstituted or monosubstituted. Typical substituents on the groups Z and R3 include C1-6 alkyl, halogen, cyano, formyl and C2-6 alkylcarbonyl; especially methyl, fluoro, cyano, formyl or acetyl.
Where R1 and R2, together with the intervening nitrogen atom, represent an optionally substituted heterocyclic ring, this ring may be unsubstituted, or substituted by one or more, preferably one or two, substituents. Examples of optional substituents on the heterocyclic ring include C1-6 alkyl, hydroxy and oxo. Typical substituents include methyl, hydroxy and oxo.
For use in medicine, the salts of the compounds, of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The term xe2x80x9chydrocarbonxe2x80x9d as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, indanyl, aryl and aryl(C1-6)alkyl.
The expression xe2x80x9ca heterocyclic groupxe2x80x9d as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl and heteroaryl(C1-6)alkyl groups.
Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d, xe2x80x9cC1-6 alkylaminoxe2x80x9d and xe2x80x9cC1-6 alkylsulphonyxe2x80x9d are to be construed accordingly.
Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl and dimethylallyl groups.
Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Typical examples of C3-7 cycloalkyl(C1-6)alkyl groups include cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.
Particular indanyl groups include indan-1-yl and indan-2-yl.
Particular aryl groups include phenyl and naphthyl, especially phenyl.
Particular aryl(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridaziyl, pyrimidinyl, pyrazinyl, pyranyl, furyl benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl oxazolyl, isoxazolyl, thiazolyl isothiazolyl imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.
The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from C1-6 alkyl, adamantyl, phenyl, halogen, C1-6 haloalkyl, C1-6 aminoalkyl, trifluoromethyl hydroxy, C1-6 alkoxy, aryloxy, oxo, C1-3 alkylenedioxy, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(C1-6)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, formyl, C2-6 alkylcarbonyl, arylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, arylsulphonyl, xe2x80x94NRvRw, xe2x80x94NRvCORw, xe2x80x94NRvCO2Rw, xe2x80x94NRvSO2Rw, xe2x80x94CH2NRvSO2Rw, xe2x80x94NHCONRvRw, xe2x80x94CONRvRw, xe2x80x94SO2NRvRw and xe2x80x94CH2SO2NRvRw, in which Rv and Rw independently represent hydrogen, C1-6 alkyl, aryl or aryl(C1-6)alkyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Typically, Y represents a chemical bond, or a xe2x80x94CH2xe2x80x94 or xe2x80x94NHCOxe2x80x94 linkage. In a particular embodiment, Y represents a chemical bond. In another embodiment, Y represents a xe2x80x94CH2xe2x80x94 linkage.
Suitable values for the substituents R1 and R2 include hydrogen, C1-6 alkyl, aryl(C1-6)alkyl and heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted. Typical substituents include C1-6 alyl, C1-6 alkoxy and halogen.
Particular values of R1 and R2 include hydrogen, methyl, ethyl and pyridinylmethyl.
Suitably, one of R1 and R2 is other than hydrogen.
Where R1 and R2, together with the intervening nitrogen atom, represent an optionally substituted heterocyclic ring, this ring is suitably a pyrrolidinyl or morpholinyl ring, either of which rings may be unsubstituted or substituted by one or more, preferably one or two, substituents, typically oxo. In this context, typical values for the xe2x80x94NR1R2 moiety include oxo-pyrrolidinyl and morpholinyl.
Suitably, the substituent Z represents an optionally substituted phenyl, pyridinyl, thienyl or imidazolyl group, or a group of formula xe2x80x94NR1R2 as defined above. Typical substituents on the moiety Z include cyano, formyl and C2-6 alkylcarbonyl, especially cyano, formyl or acetyl.
Illustrative values of Z include cyanophenyl, formylphenyl, acetylphenyl, pyridinyl, cyano-thienyl, imidazolyl, oxo-pyrrolidinyl and morpholinyl.
Representative values for the substituent Z include pyridinyl, imidazolyl, oxo-pyrrolidinyl and morpholinyl.
Suitable values for the substituent R3 include phenyl, furyl and isoxazolyl. Typical values of R3 include phenyl and furyl. A particular value of R3 is furyl.
A particular sub-class of compounds according to the invention is represented by the compounds of formula II, and salts and prodrugs thereof: 
wherein
Z1 represents an optionally substituted aryl or heteroaryl group; and
R13 represents phenyl, furyl or isoxazolyl.
The present invention also provides a compound of formula II as depicted above, or a salt or prodrug thereof, wherein
Z1 represents an optionally substituted heteroaryl group; and
R13 is as defined above.
Suitably, the substituent Z1 is unsubstituted or monosubstituted, typically unsubstituted.
Representative values of Z1 include phenyl, pyridinyl, thienyl and imidazolyl, any of which groups may be optionally substituted by one or more substituents.
Particular values for the substituent Z1 include pyridinyl, thienyl and imidazolyl, any of which groups may be optionally substituted by one or more substituents.
Examples of suitable substituents on the moiety Z1 include C1-6 alkyl, halogen, cyano, formyl and C2-6 alkylcarbonyl; especially methyl, fluoro, cyano, formyl or acetyl.
Illustrative values of Z1 include cyanophenyl, formylphenyl, acetylphenyl, pyridinyl, cyano-thienyl and imidazolyl.
A specific value of Z1 is pyridinyl. Another value of Z1 is imidazolyl.
Typically, R13 represents phenyl or furyl. In one embodiment, R13 represents furyl.
Specific compounds within the scope of the present invention include:
6-(furan-3-yl)-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine;
1-[3-(6-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]pyrrolidin-2-one;
6-(furan-3-yl)-3-[3-(imidazol-1-yl)phenyl]-3H-imidazo[4,5-b]pyridine;
6-(furan-3-yl)-3-[3-(morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-b]pyridine;
6-phenyl-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine;
1-[3xe2x80x2-(6-(furan-3-yl)imidazo[4,5-b]pyridin-3-yl)biphenyl-2-yl]ethanone;
3xe2x80x2-[6-(furan-3-yl)imidazo[4,5-b]pyridin-3-yl]biphenyl-2-carbaldehyde;
3xe2x80x2-[6-(furan-3-yl)imidazo[4,5-b]pyridin-3-yl]biphenyl-2-carbonitrile;
3-[3-(6-(furan-3-yl)imidazo[4,5-b]pyridin-3-yl)phenyl]thiophene-2-carbonitrile;
and salts and prodrugs thereof.
Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.
Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.
The binding affinity (Ki) of the compounds according to the present invention for the xcex13 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The xcex13 subunit binding affinity (Ki) of the compounds of the invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less.
The compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the xcex13 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the xcex11 subunit of the human GABAA receptor.
The potentiation of the GABA EC20 response in stably transfected cell lines expressing the xcex13 and xcex11 subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltkxe2x88x92 fibroblast cells.
The compounds according to the present invention exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10, 206-213).
The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.
In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called xe2x80x9cblood-brain barrierxe2x80x9d. Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of anxiety, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III: 
wherein Y, Z and R3 are as defined above; with formic acid, typically at an elevated temperature, e.g. a temperature in the region of 80-85xc2x0 C.
The intermediates of formula III may be prepared by reacting a compound of formula IV with a compound of formula V: 
wherein Y, Z and R3 are as defined above, and L1 represents a suitable leaving group; followed by reduction of the nitro group.
The leaving group L1 is suitably a halogen atom, e.g. chloro.
The reaction between compounds IV and V is conveniently carried out under basic conditions, for example in a mixture of 1-methyl-2-pyrrolidinone and triethylamine, or using potassium carbonate in 1,2-dichloroethane or N,N-dimethylformamide, or using triethylamine in dimethylsulphoxide, typically at an elevated temperature.
Reduction of the nitro group in the compound thereby obtained is conveniently effected by treatment with a reducing agent such as sodium sulphide nonahydrate, in which case the reaction is suitably carried out in methanol, typically in the presence of ammonium chloride at the reflux temperature of the solvent.
The compounds in accordance with the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VI with a compound of formula VII: 
wherein Z and R3 are as defined above, L2 represents a suitable leaving group, and M1 represents a boronic acid moiety xe2x80x94B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol; in the presence of a transition metal catalyst.
The leaving group L2 is typically a halogen atom, e.g. bromo.
The transition metal catalyst of use in the reaction between compounds VI and VII is suitably tetrakis(triphenylphosphine)palladium(0). The reaction is conveniently carried out at an elevated temperature in a solvent such as N,N-dimethylformamide, advantageously in the presence of potassium phosphate.
In another procedure, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VIII with a compound of formula IX: 
wherein Z and R3 are as defined above, and L3 represents a suitable leaving group; in the presence of a transition metal catalyst.
The leaving group L3 is typically trifluoromethanesulphonyloxy.
The transition metal catalyst of use in the reaction between compounds VIII and IX is suitably tris(dibenzylideneacetone)dipalladium(0). The reaction is conveniently carried out at an elevated temperature in a solvent such as N,N-dimethylacetamide, typically in the presence of 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl and potassium phosphate.
Where M1 in the intermediates of formula VI above represents a cyclic ester of a boronic acid moiety xe2x80x94B(OH)2 formed with pinacol, the relevant compound VI may be prepared by reacting bis(pinacolato)diboron with a compound of formula VIII as defined above; in the presence of a transition metal catalyst.
The transition metal catalyst of use in the reaction between bis(pinacolato)diboron and compound VIII is suitably dichloro[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]palladium(II). The reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of 1,1xe2x80x2-bis(diphenylphosphino)ferrocene and potassium acetate.
In a further procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula X with a compound of formula XI: 
wherein Y, Z and R3 are as defined above, and L4 represents a suitable leaving group; in the presence of a transition metal catalyst.
The leaving group L4 is typically a halogen atom, e.g. bromo.
The transition metal catalyst of use in the reaction between compounds X and XI is suitably tetrakis(triphenylphosphine)palladium(0), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N-dimethylformamide or a mixture of 1,3-propanediol and 1,2-dimethoxyethane, typically in the presence of potassium phosphate or sodium carbonate.
Where L4 in the compounds of formula XI above represents a halogen atom, these compounds correspond to compounds of formula I as defined above wherein R3 represents halogen, and they may therefore be prepared by any method analogous to those described above for the preparation of the compounds according to the invention.
Where L3 in the intermediates of formula VIII above represents trifluoromethanesulphonyloxy, the relevant compound VIII may be prepared by reacting the appropriate compound of formula XII: 
wherein R3 is as defined above; with trifluoromethanesulphonic anhydride, typically in the presence of pyridine.
The intermediates of formula XII above may suitably be prepared by reacting a compound of formula X as defined above with a compound of formula XIII: 
wherein L4 is as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds X and XI.
The intermediates of formula XIII above may suitably be prepared from the appropriate methoxy-substituted precursor of formula XIV: 
wherein L4 is as defined above; by treatment with hydrobromic acid, typically in acetic acid at an elevated temperature.
The intermediates of formula XIV above may suitably be prepared by reacting a compound of formula XV: 
wherein L4 is as defined above; with formic acid; under conditions analogous to those described above for the reaction between compound III and formic acid.
The intermediates of formula XV above may suitably be prepared by reacting a compound of formula XVI with the compound of formula XVII: 
wherein L1 and L4 are as defined above; followed by reduction of the nitro group; under conditions analogous to those described above in relation to the reaction between compounds IV and V.
The intermediate of formula XVHI (m-anisidine) is commercially available, e.g. from Aldrich, Gillingham, United Kingdom.
Where they are not commercially available, the starting materials of formula IV, V, VII, IX, X and XVI may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.